The chiral compound 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone has the following structure: Formula (1), which is herein also referred to as Compound 1. The “*” represents the chiral carbon.

Compound 1 and its preparation are described in WO2012/120399 (which is herein incorporated in its entirety), Example 9. The WO publication further discloses that the Formula (1) compound is chiral and that it can be used as a parasiticide for use in treating animals with a parasitic infection or infestation. In the multistep process, the compound was liberated as a precipitant comprising about 90% of the amorphous S-enantiomer and about 10% of the amorphous R-enantiomer. The amorphous S-enantiomer was obtained by precipitating out equimolar amounts of the S- and R-enantiomers, i.e., the racemate. Further, the racemate was separated by chiral HPLC. The S- and R-enantiomers obtained from the preparations were characterized by HPLC (elution time), 1H-NMR analysis, and mass spectrometry.
If a compound is to be developed as a pharmaceutical or veterinary agent, it is important to provide a form of that compound (commonly known as a drug substance or active pharmaceutical/veterinary ingredient/agent) which can be reliably prepared and purified on a large scale and which does not degrade upon storage. A crystalline, and preferably a high-melting form of the compound is therefore desirable since high-melting point crystalline solids tend to be easy to purify by crystallization and are more stable than the non-crystalline (amorphous) form.
The crystalline forms of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone have not been previously described or characterized.
Different solid-state forms of a pharmaceutical or veterinary compound can have materially different physical properties. Such differences in physical properties can have an impact, for example, on how a pharmaceutical or veterinary compound is made, processed, formulated or administered. For example, the crystalline form of one compound may have very different properties: solubility, rate of dissolution, suspension stability, stability during grinding, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration properties, desiccation, density, melting point, degradation stability, stability against phase transformation into other crystalline forms, color, and even chemical reactivity. Accordingly, the identification of new solid-state forms (i.e., crystalline forms or polymorphs) of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone that provide an advantage relative to other solid-state forms in making, processing, formulating, or administering the compound are desirable.
As described, the solid state chiral Compound 1 is about 90:10 (S:R) when synthesized. Separation of the solid state (crystal) racemate (equimolar portions of the S- and R-enantiomers) results in almost pure amorphous S-enantiomer, about 80% of the originally synthesized compound, which can then be readily crystallized, in an almost pure (˜97+%) crystal state. The S- and R-enantiomers of the racemate can be further separated by chiral HPLC and crystallized.
When crystallized, each of the S- and R-enantiomers of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone form a single anhydrous crystalline form. The crystalline form of the S-enantiomer is designated as Form A. The crystalline form of the R-enantiomer is similar to that of Form A and the solid state crystalline form of the S/R racemate is designated as the “crystalline racemate”.